La biologia del carcinoma mammario e le future implicazioni terapeutiche

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Convegno Regionale AIOM Liguria 2018

Matteo Lambertini

ESMO Fellow

Institut Jules Bordet, Brussels (Belgium)

La Biologia del Carcinoma Mammario (TN) e le Future Implicazioni Terapeutiche

Genova

29 settembre 2018

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Disclosure Information

Relationship Relevant to this Session

Lambertini, Matteo:

• Consultant or advisor: Teva

• Honoraria: Theramex

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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What is Triple Negative Breast Cancer (TNBC) ?

Schmadeka R et al, Am J Clin Pathol 2014;141:462-77

Estrogen receptor Progesterone receptor HER2

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TNBC: Histological Features

Oakman C et al, Breast 2010;19:312-21. Mills MN et al, Eur J Cancer 2018;98:48-58

Goldhirsch A et al, Ann Oncol 2011;22:1736-47

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TNBC: Transcriptomic Landscape

Prat A et al, The Oncologist2013;18:123-33

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TNBC: Transcriptomic Landscape

Lehmann BD et al, J Clin Invest 2011;121:2750-67. Lehmann BD et al, PLoS One 2016;11:e0157368

Subtype “Driver pathways” Possible sensitivity

Basal-like 1 high Ki-67; DNA damage response PARP-I and Cisplatin

Basal-like 2 GF pathways Anti-EGFR

Immunomodulatory Immune genes Immunotherapy

Mesenchymal Cell motility PI3K-mTOR Inh

Mesenchymal stem-like Cell motility; claudin-low Anti-angiogenetic

Luminal androgen receptor Steroid pathways AR antagonist

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TNBC: Genomic Landscape

Bareche Y et al, Ann Oncol 2018;29(4):895-902

Substantial biological heterogeneity in the different TNBC molecular

subtypes at the somatic mutation, copy number and gene expression levels

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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High Cell Proliferation: the TNBC Paradox

of the dose-dense schedule did not differ among tumor subtypes (P = 0.46). Most patients (80 of 107, 75%) received additional neoadjuvant chemotherapy following AC, which primarily involved either paclitaxel or docetaxel (79 of 80, or 99%). One patient received only one cycle of taxane, which was poorly tolerated, and completed the remainder of her post-AC chemotherapy with vinorelbine. It is worth noting that clinical response rates reflect only the AC contribution, whereas pathologic response rates reflect both the AC and subsequent neoadjuvant regimens. Adjuvant endocrine therapy was given to 3 of 34 (9%) patients with basal-like, 0 of 11 patients with HER2+/ER , and 61 of 62 (98%) patients with luminal tumor (P < 0.0001) subtypes.

Clinical and pathologic response to neoadjuvant anthracycline.

Table 2 il lustrates the clinical response to AC, and the pathologic response to all neoadjuvant therapies. Clinical response assessments were done after AC and did not reflect the effect of subsequent sequential drugs. Cli nical response to AC differed significantly among the subtypes (P < 0.0001), with HER2+/ ER and basal-like subtypes showing higher clinical response rates than l umi nal subtypes. Thi s di fference remained when evaluating a collapsed table comparing the dichotomized proportion of complete and partial responses to the rest (P < 0.0001). The greatest difference was seen between luminal A (39%) and basal-li ke (85%) subtypes.

Logistic regression was used to evaluate the association of age, race, disease stage, HER2+/ ER versus luminal subtype, and basal-like versus luminal (A + B combined) subtypes relative to cli nical response (complete response or partial response versus not complete response or partial response); of these, only basal-like versus luminal was significant (odds ratio, 6.6;

95% confidence interval, 2.26-19.28).

As mentioned above, most patients received subsequent taxane-based chemotherapy after AC that would not contribute to the clinical response, but may have contributed to the pathologic response. Patients who were stage II (20 of 42, 48%) were significantly more likely to receive AC alone than stage III (7 of 65, 11%; P < 0.0001). Additional chemotherapy was received by 26 of 34 (76%) patients with basal-like tumors, 10 of 11 (90%) HER2+/ER , and 44 of 62 (71%) with luminal tumors (21 of 26 luminal B, and 23 of 36 luminal A). These differences were not significant. Three of the patients did not undergo

primary surgery and thus do not have pathologic data available.

Pathologic complete response was higher in those that received subsequent chemotherapy (16 of 79, 20%) than those that did not (1 of 25, 4%; P = 0.04); the use of subsequent chemotherapy was discretionary, which limits the interpretability of this Ta b l e 2 . Breast cancer phenot ype and clinical response t o ant hracycline- based chem ot herapy

En t i r e p o p u l a t i o n

Ba sa l - l i k e ( n = 3 4 )

H ER2^* ( n = 1 1 )

Lu m i n a l B ( n = 2 6 )

Lu m i n a l A ( n = 3 6 )

P

Clinical resp onse t o AC

Com plet e response 15 ( 14% ) 10 ( 29% ) 1 ( 10% ) 2 ( 8% ) 2 ( 6% ) < 0.0001

Part ial response 50 ( 47% ) 19 ( 56 % ) 6 ( 60% ) 13 ( 50% ) 12 ( 3 3% )

St able disease 40 ( 38% ) 5 ( 15% ) 3 ( 30% ) 11 ( 42% ) 21 ( 58% )

Progressi ve disease 1 ( 1% ) 0 0 0 1 ( 3% )

Com plet e response + part ial response 65 ( 61% ) 29 ( 85% ) 7 ( 70% ) 15 ( 58% ) 14 ( 39% ) < 0.0001

Pat hologic st age post - chem ot herapy 0.0004

0 17 ( 16% ) 9 ( 27% ) 4 ( 36% ) 4 ( 15% ) 0

I 26 ( 25% ) 10 ( 31% ) 1 ( 9% ) 8 ( 31% ) 7 ( 21% )

I I 33 ( 32% ) 8 ( 24% ) 5 ( 46% ) 8 ( 31% ) 12 ( 35% )

I I I 27 ( 26% ) 6 ( 18% ) 1 ( 9% ) 5 ( 19% ) 15 ( 44% )

I V 1 ( 1% ) 0 0 1 ( 4% ) 0

*One pat ient wit h t he HER2+ / ER subt ype was not evaluable for clinical response, and t hree pat ient s did not undergo pr im ary surgery.

Fig. 1. DDFS (A) and OS (B) according to breast cancer subtype.

Chemosensit ivit y and Out com e in Breast Cancer Subt ypes

w w w .aacrjournals.org 2331 Clin Cancer Res 2007;13(8) April 15, 2007

Cancer Research.

Downloaded from

Denkert C et al, Lancet Oncol 2017;389:2430-42. Carey LA et al, Clin Cancer Res 2007;13(8):2329-34

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Pooled Analysis: recurrence by ER status

ER- Negative ER - Positive

Therapeutic Implications: Dose-Dense CT

Gray R et al, SABCS 2017

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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BRCAness/HRD/Genomic Scars

Turner NC. N Engl J Med 2017;377(25):2490-2

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Therapeutic Implications: Platinum and PARPi

Platinum-based chemotherapy

PARPi

Poggio F et al, Ann Oncol 2018;29(7):1497-508

Poggio F et al, ESMO Open 2018;3(4):e000361. Tutt A et al, Nat Med 2018;24(5):628-37

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HRD Status to Predict Treatment Response:

Conflicting Results !

Telli ML et al, Clin Cancer Res 2016;22(15):3764-73. Zhang J et al, Ann Oncol 2018;29(8):1741-7

Telli ML et al, ASCO 2018. Tutt A et al, Nat Med 2018;24(5):628-37

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Mutational Signatures of HRD: Promising Data

Combination of multiple HRD scars into HRDetect (somatic mutational signature)

Polak P et al, Nat Genet 2017;49(10):1476-86. Davies H et al, Nat Med 2017;23(4):517-25

≈1/3 of TNBC are HR deficient

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Mutational Signatures of HRD: Promising Data

Zhao EY et al, Clin Cancer Res 2017;23(24):7521-30

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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Increased Immune-Inflitrate: TILs

Denkert C et al, Lancet Oncol 2018;19(19):40-50 30%

29% 41%

19%

37%

44%

13%

32%

56%

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Therapeutic Implications: Available Data

Wein L et al, Br J Cancer 2018;119(1):4-11

Metastatic disease

Early disease

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Therapeutic Implications: Ongoing Trials

Denkert C et al, Lancet Oncol 2017;389:2430-42

TNBC

1L Nab-Paclitaxel +

placebo Nab-Paclitaxel +

Atezolizumab IMPASSION 130

NCT02425891

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Modulating the Immune-Infiltrate

Keren L et al, Cell 2018;174(6):1373-87. Kok M et al, ASCO 2018

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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Androgen Receptors

Gucalp A et al, Cancer Res 2013; 19:5505-12. Bonnefoi H et al, Ann Oncol 2016;27:812-8 Mina A et al, Onco Targets Ther 2017;10:4675-85. Traina TA et al, J Clin Oncol 2018;36(9):884-90

CBR = 19-33%

CBR = 20%

Bicalutamide

AR is present in 12% to 38% of TNBC (detectable by IHC; gene expression

analysis under development)

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Plan of the Talk

• Introduction

• Main biological features with clinical relevance 1. High cell proliferation

2. BRCAness/HRD/genomic scars 3. Increased immune-infiltrate 4. Androgen receptors

5. Other potential targets

• Conclusions

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Other Potential Targets: Genomic Aberrations

Balko JM et al, Cancer Discov 2014;4:232-45. Dent R, ASCO 2018

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Other Potential Targets: Genomic Aberrations

Schmid P et al, ASCO 2018. Kim SB et al, Lancet Oncol 2017;18(10):1360-72. Dent R, ASCO 2018

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Other Potential Targets: Epithelial Antigens

Chan JJ et al, J Oncol Pract 2018;14(5):281-9

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